Nasal delivery devices

ABSTRACT

An exhalation breath-actuated nasal delivery device for and a method of delivering a substance to a nasal cavity of a subject, the delivery device comprising: a nosepiece ( 40 ) for fitting to a nostril of a subject; a mouthpiece ( 42 ) through which the subject in use exhales; and delivery unit ( 64 ), as one of a mechanical delivery pump ( 66 ) or a nebulizer ( 115 ), for delivering a substance to the nosepiece ( 40 ); and an actuation mechanism ( 74 ) for actuating the delivery unit in response to oral exhalation through the mouthpiece, and preferably when at least one or both of the pressure at or the flow rate through the nosepiece exceeds a predetermined threshold.

[0001] The present invention relates to a nasal delivery device for anda method of delivering a substance, in particular one of a liquid, as asuspension or solution, or a powder containing a medicament, especiallysystemic or topical pharmaceuticals, a cleansing agent, or an irrigatingagent, as a liquid, preferably combined with a cleansing agent, to thenasal airway of a subject. In particular, the present invention relatesto an oral exhalation breath-actuated nasal delivery device including amechanical nasal delivery pump for delivering a substance to the nasalairway of a subject, and an oral exhalation breath-actuated nasaldelivery device including a nebulizer for delivering a substance to thenasal airway of a subject.

[0002] Referring to FIG. 1, the nasal airway 1 comprises the two nasalcavities separated by the nasal septum, which airway 1 includes numerousostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, andolfactory cells, and is lined by the nasal mucosa. The nasal airway 1can communicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in dashed line in the open position.

[0003] There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Other nasalconditions include nasal polyps which arise from the paranasal sinuses,hypertrophic adenoids, secretory otitis media, sinus disease and reducedolfaction.

[0004] In the treatment of certain nasal conditions, the topicaladministration of medicaments is preferable, particularly where thenasal mucosa is the prime pathological pathway, such as in treating orrelieving nasal congestion. Medicaments that are commonly topicallydelivered include decongestants, anti-histamines, cromoglycates,steroids and antibiotics. At present, among the known anti-inflammatorypharmaceuticals, topical steroids have been shown to have an effect onnasal congestion. Topical decongestants have also been suggested for usein relieving nasal congestion. The treatment of hypertrophic adenoidsand chronic secretory otitis media using topical decongestants, steroidsand anti-microbial agents, although somewhat controversial, has alsobeen proposed. Further, the topical administration of pharmaceuticalshas been used to treat or at least relieve symptoms of inflammation inthe anterior region of the nasopharynx, the paranasal sinuses and theauditory tubes.

[0005] Medicaments can also be systemically delivered through the nasalpathway, the nasal pathway offering a good administration route for thesystemic delivery of pharmaceuticals, such as hormones, for example,oxytocin and calcitionin, and analgetics, such as anti-migrainecompositions, as the high blood flow and large surface area of the nasalmucosa advantageously provides for rapid systemic uptake.

[0006] Nasal delivery is also expected to be advantageous for theadministration of medicaments requiring a rapid onset of action, forexample, analgetics, anti-emetics, insulin, anti-epileptics, sedativesand hypnotica, and other pharmaceuticals, for example, cardio-vasculardrugs. It is envisaged that nasal administration will provide for a fastonset of action, at a rate similar to that of injection and at a ratemuch faster than that of oral administration. Indeed, for the treatmentof many acute conditions, nasal administration is advantageous over oraladministration, since gastric stasis can further slow the onset ofaction following oral administration.

[0007] It is also expected that nasal delivery could provide aneffective delivery route for the administration of proteins and peptidesas produced by modern biotechnological techniques. For such substances,the metabolism in the intestines and the first-pass-effect in the liverrepresent significant obstacles for reliable and cost-efficiencydelivery. Furthermore, it is expected that nasal delivery using thenasal delivery technique of the present invention will prove effectivein the treatment of many common neurological diseases, such asAlzheimer's, Parkinson's, psychiatric diseases and intracerebralinfections, where not possible using existing techniques. The nasaldelivery technique of the present invention allows for delivery to theolfactory region, which region is located in the superior region of thenasal cavities and represents the only region where it is possible tocircumvent the blood-to-brain barrier (BBB) and enable communicationwith the cerebrospinal fluid (CSF) and the brain.

[0008] Also, it is expected that the nasal delivery technique of thepresent invention will allow for the effective delivery of vaccines.

[0009] Aside from the delivery of medicaments, the irrigation of thenasal mucosa with liquids, in particular saline solutions, is commonlypractised to remove particles and secretions, as well as to improve themucociliary activity of the nasal mucosa. These solutions can be used incombination with active pharmaceuticals.

[0010] For any kind of drug delivery, accurate and reliable dosing isessential, but it is of particular importance in relation to theadministration of potent drugs which have a narrow therapeutic window,drugs with potentially serious adverse affects and drugs for thetreatment of serious and life-threatening conditions. For someconditions, it is essential to individualize the dosage to theparticular situation, for example, in the case of diabetes mellitus. Fordiabetes, and, indeed, for many other conditions, the dosage of thepharmaceutical is preferably based on actual real-time measurements.Currently, blood samples are most frequently used, but the analysis ofmolecules in the exhalation breath of subjects has been proposed as analternative to blood analysis for several conditions. Breath analysis iscurrently used for the diagnosis of conditions such as helicobacterpylon infections which cause gastric ulcers.

[0011] To date, nasal medicaments have been primarily delivered as dropsor by mechanical nasal spray pumps. With mechanical spray pumps, themean particle size is typically between 40 μm and 80 μm in order toprevent the inhalation of delivered particles. In general, particlessmaller than 10 μm will bypass the nose and can be inhaled. Indeed, thenew FDA guidelines require that the fraction of particles less than 10μM be at most 5%.

[0012] Whilst the provision of a spray having a larger mean particlesize prevents the inhalation of the particles, these larger particlesare not optimal for achieving a good distribution to the nasal mucosa.

[0013] The applicant has now recognized that the closure of theoropharyngeal velum during the delivery of a substance to the nasalairway prevents the possible inhalation of the substance, therebyenabling the delivery of an aerosol having a much smaller mean particlesize than achieved by traditional nasal spray pumps. In this way, anaerosol can be generated which has an optimal particle sizedistribution.

[0014] A further advantage is that the nosepiece acts to expand thenarrowest, anterior part of the nasal cavity and thereby reduces theunwanted high deposition in the anterior region of the nasal cavitywhich is lined by squamous epithelium.

[0015] In addition, the applicant has recognized that, by establishing abidirectional flow through the nasal cavities as described inWO-A-00/51672, that is, an air flow which passes into one nostril,around the posterior margin of the nasal septum and in the oppositedirection out of the other nostril, an aerosol having an optimal flowrate and timing can be generated. Furthermore, the bidirectional airflow advantageously acts to stimulate the sensory nerves in the nasalmucosa, thereby conditioning the subject for the delivery and providinga more comfortable delivery situation.

[0016] A yet further advantage is that the air flow acts to create apositive pressure inside the nasal passages connected in series, whichtends to expand and widen narrow and congested regions.

[0017] A still yet further advantage is that the two-point fixation ofthe device in the nose with a well-fitting nozzle and in the mouthprovides a much more stable and reproducible positioning of the deviceas compared to traditional spray pumps. Thus, in addition to improveddeposition and reproducibility, the new concept provides a moreuser-friendly and intuitive nasal delivery method.

[0018] Furthermore, the delivery device, in being pre-primed andactuatable by the oral exhalation breath of a subject, does not requirethe application of an actuation force by the subject at the time ofactuation. Traditionally, mechanical liquid delivery pumps are operatedby the manual compression of a chamber containing a volume of liquid toexpel a flow of a metered volume of liquid, and mechanical powderdelivery pumps are operated by the manual compression of a chambercontaining a volume of air to drive and expel a flow of a metered amountof a dry powder. Such operation requires a relatively high actuationforce, typically of the order of 50 N, which high force often leads tosignificant movement of the delivery device, it being very difficult tomaintain a delivery device stationary when attempting to apply a highactuation force. Movement of the delivery device, both in thepositioning and orientation of the nozzle, will lead to poorreproducibility, dose accuracy and patient compliance. In beingpre-primed and actuatable by the oral exhalation breath of a subject,the delivery device of the present invention overcomes this problem.

[0019] In addition, by not requiring a subject to apply an actuationforce at the instance of delivery, the delivery device provides for thesame actuation force in each delivery, and also provides for delivery atan optimal pressure and/or flow rate, and the delivery of substancehaving an optimized particle size distribution.

[0020] Yet furthermore, in providing for the closure of theoropharyngeal velum of a subject, substance is prevented from enteringthe lower airway, and also, in a preferred embodiment, bi-directionaldelivery can be achieved through the nasal cavities.

[0021] It will be appreciated that the nasal delivery devices of thepresent invention are quite different to inhalation devices whichprovide for inhalation into the lower airway.

[0022] Inhalation devices have been used for a long time for theinhalation of medicaments in the treatment of lower airway pathologies.

[0023] One such inhalation device is the pressurized metered doseinhaler (pMDI). In such inhalers, a metered dose of medicament isreleased as an aerosol by actuating an aerosol canister, with theparticle sizes of the aerosol being required to be small, typically lessthan 5 μm, in order to reach the distal parts of the lower airway. Onedrawback with traditional pMDIs is that the subject must co-ordinateinhalation with the aerosol release in order to deliver the aerosolizedmedicament effectively to the lower airway. Inadequate co-ordinationrepresents a considerable problem, significantly reducing both lungdeposition and reproducibility. Another drawback with traditional pMDIsis the use of chlorine-containing compounds as the propellant gas, assuch gases are not environmentally friendly and have been demonstratedto destroy the ozone layer. Recently, in order to alleviate thesedrawbacks, pMDIs have been developed which use an alternative propellantgas, this being a hydrofluoroalkane (HFA), and incorporate abreath-actuation mechanism which provides for actuation of the aerosolcanister on inhalation by the subject.

[0024] Another such inhalation device is the dry powder inhaler, such asthe Turbohaler® inhaler as supplied by AstraZeneca and the Discus®inhaler as supplied by GSK. These dry powder inhalers do not requireco-ordination of delivery and inhalation and can improve deposition tothe lower airways.

[0025] Bi-directional nasal drug delivery is achieved by directing anexhaled air flow through the nasal passages in series, or by triggeringanother flow source to create such an air flow, whereas breath actuationof pulmonary drug delivery is by inhalation into a closed expandingvolume, that is, the lungs. For bi-directional nasal delivery, it isdesirable to establish the air flow before the drug is released, whereasfor inhalation, the release is best achieved at the very beginning ofinspiration to reach the most distal parts of the lungs.

[0026] Increased airway resistance in pathological conditions, both inthe pulmonary and nasal airways, is a challenge. In inhalation devices,an air flow is created by the inspiratory muscles creating a negativepressure inside the chest. In this way, air is sucked through the deviceand into the airways. For pulmonary drug delivery, it is essential thatthe triggering occurs, not only early, but also at a relatively low flowto ensure release in subjects with a very low lung capacity.Furthermore, the releasing action should require as little energy aspossible, as any resistance in the device will impede free inhalation.Still most subjects, even patients with lung diseases, will be able toachieve a flow rate of 25 L/min which is typically required to triggerthe release from a pMDI device.

[0027] For the nose, the situation is more complex and in many waysdifferent. The expiratory muscles in the thorax produce the exhaled airflow used to trigger release, and this air flow is then directed throughthe device and into the nasal passages in series, or used to triggeranother flow source. Thus, the triggering air flow is completelyreversed as compared to pulmonary breath actuation, and the air flow isdirected into another airway/compartment separated from the lowerairways.

[0028] Furthermore, the nose geometry is designed to humidify, warm andfilter the inspired air to protect the lower airways. The resistance inthe nose alone equals 50% of the total airway resistance, and theresistance may increase immensely when congested. Owing to the highanterior resistance, turbulence occurs just posterior to theconstriction, increasing deposition in this region. To achieve a betterdistribution to larger and more posterior parts of the nasal mucosa, itis envisaged to be advantageous to have the drug released at a lowerflow in a congested nose and at a higher flow in an open nose. Thisrequires a system which can be released not only by flow, but also bypressure. Such release is essential for efficient and reliableexhalation-triggered nasal drug delivery. The two main triggering modes,flow and pressure, are to certain extent overlapping. They can beincorporated in one single mechanism or provided as separate mechanisms.However, the nose may become completely blocked, in particular duringcolds and allergic attacks. In this situation, it becomes impossible toestablish a bi-directional air flow, but still it is desirable andnecessary to deliver drugs to the nose.

[0029] In one aspect the present invention provides a nasal deliverydevice for delivering a substance to a nasal cavity of a subject,comprising: a nosepiece for fitting to a nostril of a subject; amouthpiece through which the subject in use exhales; a nozzle fordirecting a substance through the nosepiece; a mechanical delivery pumpfluidly connected to the nozzle for delivering a substance to thenozzle; and an actuation mechanism for actuating the mechanical deliverypump in response to oral exhalation through the mouthpiece.

[0030] In one embodiment the actuation mechanism includes a triggermechanism for actuating the delivery pump at a predeterminable pressure.

[0031] In another embodiment the actuation mechanism includes a triggermechanism for actuating the delivery pump at a predeterminable flowrate.

[0032] In a further embodiment the actuation mechanism includes atrigger mechanism for actuating the delivery pump at one or both of apredeterminable pressure and a predeterminable flow rate.

[0033] In one embodiment the delivery device further comprises: a flowchannel fluidly connecting the nosepiece and the mouthpiece, wherebyexhaled air from an exhalation breath is in use delivered through thenosepiece.

[0034] In another embodiment the delivery device further comprises: aflow channel fluidly connected to the nosepiece through which a gasflow, separate to an exhaled air flow from an exhalation breath of thesubject, is in use delivered; and a gas supply unit for supplying a gasflow to the flow channel.

[0035] Preferably, the gas supply unit is configured to be actuated byexhalation through the mouthpiece.

[0036] In one embodiment the delivery pump comprises a liquid deliverypump for delivering a metered volume of a liquid.

[0037] In another embodiment the delivery pump comprises a powderdelivery pump for delivering a metered amount of a powder.

[0038] In one embodiment the nozzle is configured to deliver an aerosol.

[0039] In another embodiment the nozzle is configured to deliver a jet.

[0040] In another aspect the present invention provides an oralexhalation breath-actuated mechanical nasal delivery pump unit fordelivering a substance to a nasal cavity of a subject, the pump unitincluding an outlet nozzle and a mechanical delivery pump.

[0041] In one embodiment the delivery pump comprises a liquid deliverypump for delivering a metered volume of a liquid.

[0042] In another embodiment the delivery pump comprises a powderdelivery pump for delivering a metered amount of a powder.

[0043] In one embodiment the nozzle is configured to deliver an aerosol.

[0044] In another embodiment the nozzle is configured to deliver a jet.

[0045] In a further aspect the present invention provides a method ofdelivering a substance to a nasal cavity of a subject, comprising thesteps of: providing a nasal delivery device to the nasal cavity of asubject, the delivery device including a nosepiece for fitting to anostril of the subject, a mouthpiece through which the subject exhales,a nozzle for directing a substance through the nosepiece, and amechanical delivery pump fluidly connected to the nozzle for deliveringa substance to the nozzle; and actuating the delivery pump in responseto oral exhalation through the mouthpiece to deliver a substance throughthe nosepiece.

[0046] In one embodiment the step of actuating the delivery pumpcomprises the step of: actuating the delivery pump in response to oralexhalation through the mouthpiece on generation of a predeterminablepressure at the nosepiece.

[0047] In another embodiment the step of actuating the delivery pumpcomprises the step of: actuating the delivery pump in response to oralexhalation through the mouthpiece on generation of a predeterminableflow rate through the nosepiece.

[0048] In a further embodiment the step of actuating the delivery pumpcomprises the step of: actuating the delivery pump in response to oralexhalation through the mouthpiece on generation of one or both of apredeterminable pressure at or a predeterminable flow rate through thenosepiece.

[0049] In one embodiment the delivery device further comprises a flowchannel fluidly connecting the nosepiece and the mouthpiece, wherebyexhaled air from an exhalation breath is delivered through thenosepiece.

[0050] In another embodiment the method further comprises the step of:delivering a gas flow, separate to an exhaled air flow from anexhalation breath of the subject, through the nosepiece.

[0051] In one embodiment the delivery pump comprises a liquid deliverypump for delivering a metered volume of a liquid.

[0052] In another embodiment the delivery pump comprises a powderdelivery pump for delivering a metered amount of a powder.

[0053] In one embodiment the substance is delivered as an aerosol.

[0054] In another embodiment the substance is delivered as a jet.

[0055] In a yet further aspect the present invention provides a methodof delivering a substance to a nasal cavity of a subject, comprising thestep of actuating a mechanical nasal delivery pump unit, the pump unitincluding an outlet nozzle and a mechanical delivery pump fluidlyconnected thereto, on oral exhalation by the subject to deliver asubstance to a nasal cavity of the subject.

[0056] In one embodiment the delivery pump comprises a liquid deliverypump for delivering a metered volume of a liquid.

[0057] In another embodiment the delivery pump comprises a powderdelivery pump for delivering a metered amount of a powder.

[0058] In one embodiment the substance is delivered as an aerosol.

[0059] In another embodiment the substance is delivered as a jet.

[0060] In a still further aspect the present invention provides anexhalation breath-actuated nasal delivery device for delivering asubstance to a nasal cavity of a subject, comprising: a nosepiece forfitting to a nostril of a subject; a mouthpiece through which thesubject in use exhales; a nebulizer for delivering an aerosol includinga substance to the nosepiece; and an actuation unit for actuating thenebulizer when at least one or both of the pressure at or the flow ratethrough the nosepiece exceeds a predetermined threshold in response tooral exhalation through the mouthpiece.

[0061] In one embodiment the delivery device further comprises: a flowchannel fluidly connecting the nosepiece and the mouthpiece, wherebyexhaled air from an exhalation breath is in use delivered through thenosepiece.

[0062] Preferably, the actuation unit includes a flow regulator forregulating a flow of exhaled air from an exhalation breath.

[0063] In another embodiment the delivery device further comprises: aflow channel fluidly connected to the nosepiece through which a gasflow, separate to an exhaled air flow from an exhalation breath of thesubject, is in use delivered; and a gas supply unit for supplying a gasflow to the flow channel.

[0064] Preferably, the gas supply unit is configured to be actuated byexhalation through the mouthpiece.

[0065] In one embodiment the nebulizer comprises an ultrasonicnebulizer.

[0066] In another embodiment the nebulizer comprises a flow-generatednebulizer.

[0067] In a further embodiment the nebulizer comprises anelectrohydrodynamic nebulizer.

[0068] In yet another aspect the present invention provides abreath-actuated nasal delivery device, comprising: a flow channelincluding a mouthpiece through which a subject in use exhales and anosepiece for fitting to one nostril of the subject and through which anexhaled air flow is in use delivered to the nostril of the subject; anebulizer for delivering an aerosol including a substance to the flowchannel; and a trigger mechanism for actuating the nebulizer when thepressure and/or flow of the air exhaled through the mouthpiece exceeds apredeterminable threshold.

[0069] In a still yet further aspect the present invention provides amethod of delivering a substance to a nasal cavity of a subject,comprising the steps of: providing a nasal delivery device comprising anosepiece for fitting to a nostril of a subject, a mouthpiece throughwhich the subject exhales, and a nebulizer for delivering an aerosolincluding a substance to the nosepiece; and actuating the nebulizer whenat least one or both of the pressure at or the flow rate through thenosepiece exceeds a predetermined threshold in response to oralexhalation through the mouthpiece.

[0070] In one embodiment the delivery device further comprises a flowchannel fluidly connecting the nosepiece and the mouthpiece, wherebyexhaled air from an exhalation breath is delivered through thenosepiece.

[0071] Preferably, the delivery device further comprises a flowregulator for regulating a flow of exhaled air from an exhalationbreath.

[0072] In another embodiment the method further comprises the step of:delivering a gas flow, separate to an exhaled air flow from anexhalation breath of the subject, through the nosepiece.

[0073] In one embodiment the nebulizer comprises an ultrasonicnebulizer.

[0074] In another embodiment the nebulizer comprises a flow-generatednebulizer.

[0075] In a further embodiment the nebulizer comprises anelectrohydrodynamic nebulizer.

[0076] Preferred embodiments of the present invention will now bedescribed hereinbelow by way of example only with reference to theaccompanying drawings, in which:

[0077]FIG. 1 diagrammatically illustrates the upper airway of a humansubject;

[0078] FIGS. 2(a) to (d) illustrate an exhalation breath-actuated nasaldelivery device in accordance with a first embodiment of the presentinvention;

[0079] FIGS. 3(a) to (d) illustrate an exhalation breath-actuated nasaldelivery device in accordance with a second embodiment of the presentinvention;

[0080]FIG. 4 illustrates an exhalation breath-actuated nasal deliverydevice in accordance with a third embodiment of the present invention;and

[0081]FIG. 5 illustrates an exhalation breath-actuated nasal deliverydevice in accordance with a fourth embodiment of the present invention.

[0082] FIGS. 2(a) to (d) illustrate an oral exhalation breath-actuatednasal delivery device in accordance with a first embodiment of thepresent invention.

[0083] The delivery device comprises a housing 32 which includes achamber 34 for receiving the exhalation breath of a subject, a nosepiece40 for fitting in a nostril of the subject which is in fluidcommunication with the chamber 34 in the housing 32 and disposed to one,the distal, end of the housing 32, and a mouthpiece 42 through which thesubject exhales and which is in fluid communication with the chamber 34in the housing 32.

[0084] The nosepiece 40 is an expandable member which is configured toexpand on exhalation through the mouthpiece 42 such as to promote asealing fit between the nosepiece 40 and a nostril of a subject, withsuch a sealing fit only being achievable on the nosepiece 40 firstlybeing sufficiently inserted into the nostril of the subject foreffective operation of the delivery device. Where the nosepiece 40 isnot sufficiently inserted into a nostril of a subject for effectiveoperation of the delivery device, exhaled air from the exhalation breathof the subject escapes to the atmosphere between the outer peripheralsurface of the nosepiece 40 and the nostril of the subject. In thisembodiment the nosepiece 40 comprises an enclosed, gas-filled annularmember, the outer surface 44 and at least a part of the inner surface 46of which are flexible elements, in this embodiment resilient elements,such that the pressure generated in the chamber 34 in the housing 32 bythe exhalation breath of a subject acts on the flexible inner surface 46of the nosepiece 40 to cause the flexible outer surface 44 of thenosepiece 40 to expand outwardly into contact with the nostril of thesubject, and thereby both seal the nosepiece 40 to the nostril of thesubject and expand the nostril, and hence the nasal airway, of thesubject. By providing for the escape of exhaled air from the exhalationbreath of a subject through the nostril of the subject when thenosepiece 40 is not sufficiently inserted in the nostril of the subjectfor effective operation of the delivery device, the pressure which canbe developed in the chamber 34 in the housing 32 by the subject isinsufficient to actuate the delivery device, as will be described inmore detail hereinbelow. When the nosepiece 40 is sufficiently insertedin a nostril of a subject for effective operation of the deliverydevice, the exhaled air from the exhalation breath of the subject has nomeans of escape other than through the nostril of the subject, andthereby allows for actuation of the delivery device on generation of apredetermined actuation pressure within the chamber 34 in the housing32.

[0085] The delivery device further comprises a nozzle 56 for providingan aerosol through the nosepiece 40. The nozzle 56 comprises a head 58which is located, in this embodiment co-axially, within the nosepiece40, and a delivery tube 62 which is fluidly connected to the head 58. Inan alternative embodiment the nozzle 56 could be configured to provide ajet of a substance through the nosepiece 40.

[0086] The delivery device further comprises a substance supply unit 64for delivering a metered dose of a substance to the nozzle 56.

[0087] The substance supply unit 64 comprises a mechanical delivery pump66 which is fluidly connected to the nozzle 56 and configured, onactuation thereof, to deliver a metered dose of a substance to thenozzle 56, which nozzle 56 generates an aerosol. The delivery pump 66 ismovable relative to the nozzle 56 from a first, non-actuated position(as illustrated in FIGS. 2(a) to (c)) to a second, actuated position (asillustrated in FIG. 2(d)) to deliver a metered dose of a substance tothe nozzle 56, and hence generate an aerosol.

[0088] In this embodiment the mechanical delivery pump 66 comprises aliquid delivery pump for delivering a metered volume of a liquid, here aliquid containing a medicament, either as a suspension or solution, tothe nozzle 56 on actuation thereof.

[0089] In an alternative embodiment the mechanical delivery pump 66could comprise a powder delivery pump for delivering a metered amount ofa powder, here a powder containing a medicament, to the nozzle 56 onactuation thereof.

[0090] The substance supply unit 64 further comprises a biasing element68, in this embodiment a resilient element, particularly a compressionspring, for biasing the delivery pump 66 in an actuating direction whenin the non-actuated position, and a loading mechanism 70, in thisembodiment comprising first and second levers, for loading the biasingelement 68 such as to bias the delivery pump 66, when in thenon-actuated position, with an actuation force. The loading mechanism 70is movable between a first, rest position in which the biasing element68 is not loaded thereby, and a second, operative position in which thebiasing element 68, when restrained by the delivery pump 66, loads thedelivery pump 66 with the actuation force.

[0091] The delivery device further comprises a trigger mechanism 74which is configured to be actuatable to cause the actuation of thesubstance supply unit 64. In this embodiment the trigger mechanism 74 isconfigured to be actuatable to cause the actuation of the substancesupply unit 64 on the generation of a predetermined pressure in thechamber 34 in the housing 32. In an alternative embodiment the triggermechanism 74 could be configured to be actuatable to cause the actuationof the substance supply unit 64 on the generation of a predeterminedflow rate through the mouthpiece 42.

[0092] The trigger mechanism 74 comprises first and second stop members76, 78, and first and second biasing elements 80, 82, in this embodimentresilient elements, particularly compression springs, which act to biasrespective ones of the first and second stop members 76, 78 inwardly toa stop position (as illustrated in FIGS. 2(a) to (c)) in which the firstand second stop members 76, 78 act to prevent movement of the deliverypump 66 from the non-actuated position to the actuated position.

[0093] The trigger mechanism 74 further comprises first and second arms86, 88 which are pivotable about respective pivots 90, 92 and coupled atone end thereof to respective ones of the first and second stop members76, 78 such that pivoting of the arms 86, 88 to a release positioncauses the respective ones of the stop members 76, 78 to which the arms86, 88 are coupled to be moved outwardly against the bias of the firstand second biasing elements 80, 82 to a release position (as illustratedin FIG. 2(d)) in which the stop members 76, 78 are disposed outwardly ofthe head of the delivery pump 66, such that the delivery pump 66, whenbiased by the biasing element 68, is driven to the actuated position. Inbeing driven to the actuated position, a metered dose of a substance isdelivered from the delivery pump 66 to the nozzle 56, with the nozzle 56acting to generate an aerosol.

[0094] The trigger mechanism 74 further comprises a diaphragm 96, inthis embodiment a resilient member, which defines a part of the wall ofthe chamber 34 in the housing 32.

[0095] The diaphragm 96 is configured such as, on generation of apredetermined actuation pressure within the chamber 34 in the housing32, to be deflected such as to engage the other, distal ends of the arms86, 88 and cause the same to be pivoted to the release position. Thisactuation pressure cannot be achieved until the nosepiece 40 issufficiently inserted in a nostril of a subject for effective operationof the delivery device, in which position the escape of exhaled air fromthe exhalation breath of the subject directly to the atmosphere isprevented. Whilst the nosepiece 40 is not sufficiently inserted into anostril of a subject as to provide for effective operation of thedelivery device, exhaled air from the exhalation breath of the subjectescapes to the atmosphere, thereby preventing the development of theactuation pressure within the chamber 34 in the housing 32.

[0096] With this configuration, the delivery device, in being pre-primedand actuatable by the oral exhalation breath of a subject, does notrequire the application of an actuation force by the subject at theinstance of actuation, and provides for the closure of the oropharyngealvelum of the subject. Traditionally, mechanical liquid delivery pumpsare operated by the manual compression of a chamber containing a volumeof liquid to expel a flow of a metered volume of liquid, and mechanicalpowder delivery pumps are operated by the manual compression of achamber containing a volume of air to drive and expel a flow of ametered amount of a dry powder. Such operation requires a relativelyhigh actuation force, typically of the order of 50 N, which high forceoften leads to significant movement of the nasal delivery device, itbeing very difficult to maintain a nasal delivery device stationary whenattempting to apply a high actuation force. Movement of the deliverydevice, both in the positioning and orientation of the nozzle, will leadto poor reproducibility, dose accuracy and patient compliance. In beingpre-primed and actuatable by the oral exhalation breath of a subject,the delivery device of the present invention overcomes this problem,and, in having two points of fixation, namely at the nosepiece 40 andthe mouthpiece 42, positioning and orientation of the delivery devicecan be ensured. In addition, by not requiring a subject to apply anactuation force at the instance of actuation, the delivery deviceprovides for the same actuation force in each delivery, and alsoprovides for delivery at an optimal pressure and/or flow rate, and thedelivery of substance having an optimized particle size distribution.Furthermore, in providing for the closure of the oropharyngeal velum ofa subject, substance is prevented from entering the lower airway, andalso, in a preferred embodiment, bi-directional delivery can be achievedthrough the nasal cavities.

[0097] FIGS. 3(a) to (d) illustrate an oral exhalation breath-actuatednasal delivery device in accordance with a second embodiment of thepresent invention.

[0098] The delivery device of this embodiment is very similar to thedelivery device of the above-described first embodiment, and thus, inorder to avoid unnecessary duplication of description, only thedifferences will be described in detail, with like reference signsdesignating like parts.

[0099] The delivery device of this embodiment differs from that of theabove-described first embodiment in further comprising an oralexhalation breath-actuatable gas supply unit 98 for delivering a gasflow to the chamber 34 in the housing 32 in response to exhalation by asubject, and in that the mouthpiece 42 is in fluid communication withthe gas supply unit 98 and not the chamber 34 in the housing 32, wherebya controlled gas flow is delivered to the chamber 34 in the housing 32,and hence the nasal airway of a subject, from the gas supply unit 98 inresponse to exhalation through the mouthpiece 42.

[0100] Operation of the delivery device is the same as for theabove-described first embodiment, with a gas flow being delivered to thechamber 34 in the housing 32, and hence a gas flow being developed inthe nasal airway, by the gas supply unit 98 in response to exhalationthrough the mouthpiece 42.

[0101]FIG. 4 illustrates an oral exhalation breath-actuated nasaldelivery device in accordance with a third embodiment of the presentinvention.

[0102] The delivery device comprises a nosepiece 101 for fitting in onenostril of a subject to provide a fluid-tight seal therewith, amouthpiece 103 through which the subject exhales, and a flow channel 105which fluidly connects the nosepiece 101 and the mouthpiece 103. Withthis configuration, exhaled air from an exhalation breath of a subjectis delivered through the nasal airway of the subject.

[0103] In this embodiment the delivery device further comprises a filterunit 107 which is disposed at the inlet end of the flow channel 105,here including a moisture filter. In a preferred embodiment the filterunit 107 could include an anti-microbial filter.

[0104] The delivery device further comprises a pressure detector 109, inthis embodiment an electronic pressure detector, which is disposed inthe flow channel 105, in this embodiment downstream of the filter unit107, for detecting the pressure developed in the flow channel 105 onexhalation therethrough by the subject.

[0105] The delivery device further comprises a flow meter 111, in thisembodiment an electronic flow meter, which is disposed in the flowchannel 105, in this embodiment downstream of the filter unit 107, fordetecting the flow rate in the flow channel 105 on exhalationtherethrough by the subject.

[0106] The delivery device further comprises a flow regulator 113 whichis disposed upstream of the pressure sensor 109 and actuatable tocontrol the flow rate of the exhaled air flow. In this embodiment theflow regulator 113 includes an electrically-operable baffle which ismovable, in the flow channel 105 to restrict the flow therethrough andthereby enable control of the flow rate to predeterminable values.

[0107] The delivery device further comprises a nebulizer 115 which is influid communication with the flow channel 105, in this embodimentupstream of the flow meter 111, and actuatable to deliver a metered doseof a substance as an aerosol.

[0108] In this embodiment the nebulizer 115 comprises an ultrasonicnebulizer, whereby a liquid aerosol is generated by the vibration of aliquid supply, here a liquid containing a medicament, either as asolution or suspension, at a predetermined frequency, typicallyutilizing a piezo-electric element, with the frequency determining theparticle size distribution of the delivered aerosol.

[0109] In another embodiment the nebulizer 115 could comprise aflow-induced nebulizer, whereby a gas flow interacts with a liquidsupplied from a nozzle to generate a liquid aerosol, with the flow rateand the nozzle geometry determining the particle size distribution ofthe delivered aerosol.

[0110] In a further embodiment the nebulizer 115 could comprise anelectrohydrodynamic (EHD) nebulizer, such nebulizers being capable ofgenerating aerosols from liquid solutions or suspensions. In thisnebulizer, flows of liquid are charged by an electric field, whichcharge builds up on the liquid surface, such that, when the liquid flowsexit the respective nozzles, the repelling force of the surface chargeovercomes the surface tension of the liquid and develops a fine aerosol.The particle size distribution of the aerosol can be controlled byadjusting a number of variables, such as physical and chemicalproperties of the drug formulations, the operating conditions and theelectric field.

[0111] The delivery device further comprises a control unit 117 which isoperably coupled to the pressure sensor 109, the flow meter 111, theflow regulator 113 and the nebulizer 115. The control unit 117 isconfigured to monitor the pressure detected by the pressure sensor 109and the flow rate detected by the flow meter 111, and actuate thenebulizer 115 on the establishment of one or both of a predeterminedpressure at and a predetermined flow rate through the flow channel 105,thereby providing for optimal delivery of substance to the nasal airwayof a subject.

[0112] Operation of the delivery device will now be describedhereinbelow.

[0113] A subject fits the nosepiece 101 to one nostril and grips themouthpiece 103 in the mouth. The subject then exhales through themouthpiece 103 such as to deliver the air flow from an exhalation breaththrough the flow channel 105 and the nasal airway of the subject, inthis embodiment a bi-directional air flow through the nasal cavities ofthe nasal airway, with the exhaled air flow first being filtered by thefilter unit 107. The control unit 117 monitors the pressure detected bythe pressure sensor 109 and the flow rate detected by the flow meter111, and actuates the nebulizer 115 on the establishment of one or bothof a predetermined pressure at and a predetermined flow rate through theflow channel 105, thereby providing for optimal delivery of thesubstance to the nasal airway.

[0114]FIG. 5 illustrates an oral exhalation breath-actuated nasaldelivery device in accordance with a fourth embodiment of the presentinvention.

[0115] The delivery device comprises a nosepiece 101 for fitting in onenostril of a subject to provide a fluid-tight seal therewith, amouthpiece 103 through which the subject exhales, a first flow channel105 which is fluidly connected to the nosepiece 101, and a second flowchannel 106 which is fluidly connected to the mouthpiece 103.

[0116] The delivery device further comprises a first pressure detector109, in this embodiment an electronic pressure detector, which isdisposed in the second flow channel 106 for detecting the generation ofa predetermined pressure in the second flow channel 106 on exhalation bythe subject therethrough; this pressure being indicative of themaintenance of an exhalation flow which is such as to maintain theoropharyngeal velum in the closed position, as is necessary for abi-directional flow through the nasal cavities of a subject.

[0117] The delivery device further comprises a second pressure detector110, in this embodiment an electronic pressure detector, which isdisposed in the first flow channel 105 for detecting the pressuretherein.

[0118] The delivery device further comprises a flow meter 111, in thisembodiment an electronic flow meter, which is disposed in the first flowchannel 105, in this embodiment downstream of the second pressuredetector 110, for detecting the flow rate in the first flow channel 105.

[0119] The delivery device further comprises a regulatable gas supplyunit 112 which is fluidly connected to the first flow channel 105, inthis embodiment upstream of the second pressure detector 110, fordelivering a controlled gas flow through the first flow channel 105, andhence the nasal airway of a subject.

[0120] The delivery device further comprises a nebulizer 115 which is influid communication with the first flow channel 105, in this embodimentdownstream of the flow meter 111, and actuatable to deliver a metereddose of a substance.

[0121] In this embodiment the nebulizer 15 comprises an ultrasonicnebulizer, whereby a liquid aerosol is generated by the vibration of aliquid supply, here a liquid containing a medicament, either as asolution or suspension, at a predetermined frequency, typicallyutilizing a piezo-electric element, with the frequency determining theparticle size distribution of the delivered aerosol.

[0122] In another embodiment the nebulizer 115 could comprise aflow-induced nebulizer, whereby a gas flow interacts with a liquidsupplied from a nozzle to generate a liquid aerosol, with the flow rateand the nozzle geometry determining the particle size distribution ofthe delivered aerosol.

[0123] In a further embodiment the nebulizer 115 could comprise anelectrohydrodynamic (EHD) nebulizer, such nebulizers being capable ofgenerating aerosols from liquid solutions or suspensions. In thisnebulizer, flows of liquid are charged by an electric field, whichcharge builds up on the liquid surface, such that, when the liquid flowsexit the respective nozzles, the repelling force of the surface chargeovercomes the surface tension of the liquid and develops a fine aerosol.The particle size distribution of the aerosol can be controlled byadjusting a number of variables, such as physical and chemicalproperties of the drug formulations, the operating conditions and theelectric field.

[0124] The delivery device further comprises a control unit 117 which isoperably coupled to the first and second pressure sensors 109, 110, theflow meter 111, the regulatable gas supply unit 112 and the nebulizer115. The control unit 117 is configured to monitor the pressure detectedby the second pressure sensor 110 and the flow rate detected by the flowmeter 111, and actuate the nebulizer 115 on the establishment of one orboth of a predetermined pressure at and a predetermined flow ratethrough the first flow channel 105, thereby providing for optimaldelivery of a substance to the nasal airway of a subject. In thisembodiment the control unit 117 is configured to enable actuation of thegas supply unit 112 and the nebulizer 115 only on detection of apredetermined pressure by the first pressure sensor 109; this pressurebeing indicative that the subject is exhaling through the mouthpiece 103with sufficient force as to close the oropharyngeal velum of thesubject, and thereby prevent delivery to the lower airway and ensurebi-directional delivery through the nasal cavities of the subject.

[0125] Operation of the delivery device will now be describedhereinbelow.

[0126] A subject fits the nosepiece 101 to one nostril and grips themouthpiece 103 in the mouth.

[0127] The subject then exhales through the mouthpiece 103, whichexhalation is such as to cause closure of the oropharyngeal velum of thesubject. On detection of a predetermined pressure by the first pressuresensor 109, the control unit 117 actuates the gas supply unit 112 todeliver a gas flow having a predetermined flow rate such as to deliver agas flow through the first flow channel 105 and the nasal airway of thesubject, in this embodiment a bi-directional air flow through the nasalcavities of the nasal airway. The control unit 117 monitors the pressuredetected by the second pressure sensor 110 and the flow rate detected bythe flow meter 111, and actuates the nebulizer 115 on the establishmentof one or both of a predetermined pressure at and a predetermined flowrate through the first flow channel 105, thereby providing for optimaldelivery of a substance to the nasal airway.

[0128] Finally, it will be understood that the present invention hasbeen described in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the claimed inventionas defined by the appended claims.

[0129] For example, it will be understood that the present inventionfinds application in multi-dose or single-dose delivery devices, inparticular multi-dose and single-dose delivery pumps.

1. An exhalation breath-actuated nasal delivery device for delivering asubstance to a nasal cavity of a subject, comprising: a nosepiece forfitting to a nostril of a subject; a mouthpiece through which thesubject in use exhales; a nozzle for directing a substance through thenosepiece; a mechanical delivery pump fluidly connected to the nozzlefor delivering a substance to the nozzle; and an actuation mechanism foractuating the mechanical delivery pump in response to oral exhalationthrough the mouthpiece.
 2. The delivery device of claim 1, wherein theactuation mechanism includes a trigger mechanism for actuating thedelivery pump at a predeterminable pressure.
 3. The delivery device ofclaim 1, wherein the actuation mechanism includes a trigger mechanismfor actuating the delivery pump at a predeterminable flow rate.
 4. Thedelivery device of claim 1, wherein the actuation mechanism includes atrigger mechanism for actuating the delivery pump at one or both of apredeterminable pressure and a predeterminable flow rate.
 5. Thedelivery device of any of claims 1 to 4, further comprising: a flowchannel fluidly connecting the nosepiece and the mouthpiece, wherebyexhaled air from an exhalation breath is in use delivered through thenosepiece.
 6. The delivery device of any of claims 1 to 4, furthercomprising: a flow channel fluidly connected to the nosepiece throughwhich a gas flow, separate to an exhaled air flow from an exhalationbreath of the subject, is in use delivered; and a gas supply unit forsupplying a gas flow to the flow channel.
 7. The delivery device ofclaim 6, wherein the gas supply unit is configured to be actuated byexhalation through the mouthpiece.
 8. The delivery device of any ofclaims 1 to 7, wherein the delivery pump comprises a liquid deliverypump for delivering a metered volume of a liquid.
 9. The delivery deviceof any of claims 1 to 7, wherein the delivery pump comprises a powderdelivery pump for delivering a metered amount of a powder.
 10. Thedelivery device of any of claims 1 to 9, wherein the nozzle isconfigured to deliver an aerosol.
 11. The delivery device of any ofclaims 1 to 9, wherein the nozzle is configured to deliver a jet.
 12. Anoral exhalation breath-actuated mechanical nasal delivery pump unit fordelivering a substance to a nasal cavity of a subject, the pump unitincluding an outlet nozzle and a mechanical delivery pump.
 13. Thedelivery pump unit of claim 12, wherein the delivery pump comprises aliquid delivery pump for delivering a metered volume of a liquid. 14.The delivery pump unit of claim 12, wherein the delivery pump comprisesa powder delivery pump for delivering a metered amount of a powder. 15.The delivery pump unit of any of claims 12 to 14, wherein the nozzle isconfigured to deliver an aerosol.
 16. The delivery pump unit of any ofclaims 12 to 14, wherein the nozzle is configured to deliver a jet. 17.A method of delivering a substance to a nasal cavity of a subject,comprising the steps of: providing a nasal delivery device to the nasalcavity of a subject, the delivery device including a nosepiece forfitting to a nostril of the subject, a mouthpiece through which thesubject exhales, a nozzle for directing a substance through thenosepiece, and a mechanical delivery pump fluidly connected to thenozzle for delivering a substance to the nozzle; and actuating thedelivery pump in response to oral exhalation through the mouthpiece todeliver a substance through the nosepiece.
 18. The method of claim 17,wherein the step of actuating the delivery pump comprises the step of:actuating the delivery pump in response to oral exhalation through themouthpiece on generation of a predeterminable pressure at the nosepiece.19. The method of claim 17, wherein the step of actuating the deliverypump comprises the step of: actuating the delivery pump in response tooral exhalation through the mouthpiece on generation of apredeterminable flow rate through the nosepiece.
 20. The method of claim17, wherein the step of actuating the delivery pump comprises the stepof: actuating the delivery pump in response to oral exhalation throughthe mouthpiece on generation of one or both of a predeterminablepressure at or a predeterminable flow rate through the nosepiece. 21.The method of any of claims 17 to 20, wherein: the delivery devicefurther comprises a flow channel fluidly connecting the nosepiece andthe mouthpiece, whereby exhaled air from an exhalation breath isdelivered through the nosepiece.
 22. The method of any of claims 17 to20, further comprising the step of: delivering a gas flow, separate toan exhaled air flow from an exhalation breath of the subject, throughthe nosepiece.
 23. The method of any of claims 17 to 22, wherein thedelivery pump comprises a liquid delivery pump for delivering a meteredvolume of a liquid.
 24. The method of any of claims 17 to 22, whereinthe delivery pump comprises a powder delivery pump for delivering ametered amount of a powder.
 25. The method of any of claims 17 to 24,wherein the substance is delivered as an aerosol.
 26. The method of anyof claims 17 to 24, wherein the substance is delivered as a jet.
 27. Amethod of delivering a substance to a nasal cavity of a subject,comprising the step of actuating a mechanical nasal delivery pump unit,the pump unit including an outlet nozzle and a mechanical delivery pumpfluidly connected thereto, on oral exhalation by the subject to delivera substance to a nasal cavity of the subject.
 28. The method of claim27, wherein the delivery pump comprises a liquid delivery pump fordelivering a metered volume of a liquid.
 29. The method of claim 27,wherein the delivery pump comprises a powder delivery pump fordelivering a metered amount of a powder.
 30. The method of any of claims27 to 29, wherein the substance is delivered as an aerosol.
 31. Themethod of any of claims 27 to 29, wherein the substance is delivered asa jet.
 32. An exhalation breath-actuated nasal delivery device fordelivering a substance to a nasal cavity of a subject, comprising: anosepiece for fitting to a nostril of a subject; a mouthpiece throughwhich the subject in use exhales; a nebulizer for delivering an aerosolincluding a substance to the nosepiece; and an actuation unit foractuating the nebulizer when at least one or both of the pressure at orthe flow rate through the nosepiece exceeds a predetermined threshold inresponse to oral exhalation through the mouthpiece.
 33. The deliverydevice of claim 32, further comprising: a flow channel fluidlyconnecting the nosepiece and the mouthpiece, whereby exhaled air from anexhalation breath is in use delivered through the nosepiece.
 34. Thedelivery device of claim 33, wherein the actuation unit includes a flowregulator for regulating a flow of exhaled air from an exhalationbreath.
 35. The delivery device of claim 32, further comprising: a flowchannel fluidly connected to the nosepiece through which a gas flow,separate to an exhaled air flow from an exhalation breath of thesubject, is in use delivered; and a gas supply unit for supplying a gasflow to the flow channel.
 36. The delivery device of claim 35, whereinthe gas supply unit is configured to be actuated by exhalation throughthe mouthpiece.
 37. The delivery device of any of claims 32 to 36,wherein the nebulizer comprises an ultrasonic nebulizer.
 38. Thedelivery device of any of claims 32 to 36, wherein the nebulizercomprises a flow-generated nebulizer.
 39. The delivery device of any ofclaims 32 to 36, wherein the nebulizer comprises an electrohydrodynamicnebulizer.
 40. A method of delivering a substance to a nasal cavity of asubject, comprising the steps of: providing a nasal delivery devicecomprising a nosepiece for fitting to a nostril of a subject, amouthpiece through which the subject exhales, and a nebulizer fordelivering an aerosol including a substance to the nosepiece; andactuating the nebulizer when at least one or both of the pressure at orthe flow rate through the nosepiece exceeds a predetermined threshold inresponse to oral exhalation through the mouthpiece.
 41. The method ofclaim 40, wherein: the delivery device further comprises a flow channelfluidly connecting the nosepiece and the mouthpiece, whereby exhaled airfrom an exhalation breath is delivered through the nosepiece.
 42. Themethod of claim 41, wherein: the delivery device further comprises aflow regulator for regulating a flow of exhaled air from an exhalationbreath.
 43. The method of claim 40, further comprising the step of:delivering a gas flow, separate to an exhaled air flow from anexhalation breath of the subject, through the nosepiece.
 44. The methodof any of claims 40 to 43, wherein the nebulizer comprises an ultrasonicnebulizer.
 45. The method of any of claims 40 to 43, wherein thenebulizer comprises a flow-generated nebulizer.
 46. The method of any ofclaims 40 to 43, wherein the nebulizer comprises an electrohydrodynamicnebulizer.
 47. A nasal delivery device for delivering a substance to anasal cavity of a subject substantially as hereinbefore described withreference to any of FIGS. 2(a) to (d), FIGS. 3(a) to (d), FIG. 4 or FIG.5 of the accompanying drawings.
 48. A method of delivering a substanceto a nasal cavity of a subject substantially as hereinbefore describedwith reference to any of FIGS. 2(a) to (d), FIGS. 3(a) to (d), FIG. 4 orFIG. 5 of the accompanying drawings.